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Podcast for Healthcare Professionals: New Boxed Warning on severe liver injury with propylthiouracil

Welcome, my name is Catherine Chew, a pharmacist in the Division of Drug Information. I am updating you about a new Boxed Warning and risk management plan for propylthiouracil.

FDA has now added a Boxed Warning to the label for propylthiouracil, a drug used to treat hyperthyroidism, to include information about reports of severe liver injury and acute liver failure, some of which have been fatal, in adult and pediatric patients using this medication.

The new warning also states that for patients being started on treatment it may be appropriate to reserve the use of propylthiouracil for those who cannot tolerate other treatments such as methimazole, radioactive iodine or surgery.

In addition, due to the occurrence of birth defects that have been observed with the use of methimazole during the first trimester of pregnancy, propylthiouracil may be the treatment of choice during and just before the first trimester of pregnancy.

To help patients understand the known benefits and potential risks of this medication, as part of a Risk Evaluation and Mitigation Strategy (REMS), FDA is requiring that a Medication Guide be given to every patient filling a prescription for propylthiouracil.

In 2008 and 2009, FDA, the National Institute of Child Health and Human Development, the American Thyroid Association, and other stakeholders held meetings to discuss the available data on severe liver injury and propylthiouracil use. In June 2009, FDA issued a communication to Healthcare Professionals about severe liver injury and propylthiouracil use. In addition, FDA Patient Safety News featured information about this safety issue in August 2009.

To better understand the potential for liver injury with propylthiouracil, FDA conducted a search of postmarketing adverse event reports for propylthiouracil submitted to the agency from 1969, when the Adverse Events Reporting System (AERS) database began tracking adverse event reports, to June 2009. FDA also evaluated postmarketing adverse event reports on methimazole—the only other approved treatment for hyperthyroidism--from 1969 to June 2009.

The agency identified 34 cases of severe liver injury associated with propylthiouracil. Twenty-three cases were in adult patients and 11 were in pediatric patients. Of the 23 adult cases, 13 deaths and five liver transplants were reported. Among the 11 pediatric cases, two cases resulted in death and seven patients required a liver transplant; one patient died while on the transplant list. FDA identified five cases of severe liver injury reported with methimazole. All five cases were in adult patients and three resulted in death. Based on these findings, and a review of the medical literature, the agency concluded that use of propylthiouracil is associated with a higher risk for clinically serious or fatal liver injury compared to methimazole in both adult and pediatric patients.

Although the number of identified reports of postmarketing cases of severe liver injury with propylthiouracil use between 1969 to 2009 is 34, FDA included information about this adverse event in the Boxed Warning due to the severity of the cases, some of which have been fatal, and to ensure that healthcare professionals are aware of this risk and are vigilant for the signs and symptoms of hepatic toxicity.

To better understand use in pregnancy, the agency also reviewed post-marketing data to better understand the potential for birth defects from propylthiouracil or methimazole.

FDA's review found that congenital malformations were reported approximately three times more often with prenatal exposure to methimazole compared to propylthiouracil (29 cases with methimazole and 9 cases with propylthiouracil). In addition, there was a distinct and consistent pattern of congenital malformations associated with the use of methimazole, but not with propylthiouracil. Approximately 90% of the congenital malformations with methimazole were craniofacial malformations. In the majority of cases, there were multiple malformations which frequently included a combination of craniofacial defects and gastrointestinal atresias or aplasias. These specific birth defects were associated with the use of methimazole during the 1st trimester. They were not found when the drug was given later in pregnancy.

The agency did not find a consistent pattern of birth defects associated with the use of propylthiouracil. FDA concluded there is no convincing evidence of an association between propylthiouracil use and congenital malformations, even with use during the 1st trimester.

At this time, FDA recommends that Healthcare Professionals:

1. Be aware that severe liver injury and acute liver failure, including fatal cases, have been reported in adult and pediatric patients taking propylthiouracil.

2. When initiating hyperthyroid treatment, propylthiouracil should be reserved for patients who cannot tolerate methimazole or for patients for whom radioactive iodine therapy or surgery is not appropriate treatment.

3. Propylthiouracil may be the treatment of choice when an antithyroid drug is needed during and just prior to the 1st trimester of pregnancy. Fetal abnormalities have been seen with methimazole use during the first trimester of pregnancy.

4. Propylthiouracil is not recommended for use in pediatric patients, except in rare instances in which other alternative treatments are not appropriate.

5. Encourage patients to read the Medication Guide when picking up their prescription for propylthiouracil.

6. Review the newly revised label for complete information on the use of propylthiouracil.

7. Report any adverse events with the use of propylthiouracil to FDA's MedWatch program at www.fda.gov/medwatch.

Thank you for listening. The FDA is committed to keeping healthcare professionals informed of the latest safety information. If you have questions about this safety communication, you can reach the Division of Drug Information at the following email address: druginfo@fda.hhs.gov.